ABSTRACT Prevalence of Alzheimer?s disease (AD) and related dementias is expected to triple over the next 30 years, with the largest burden placed on high-risk racial/ethnic minorities. Despite troubling epidemiologic and economic projections, there are no effective treatments on the horizon. Substantial barriers to their development include the lack of early biomarkers and data elucidating the role of cardiovascular disease (CVD) in cognitive decline. It is estimated that >65% of AD cases have a ?mixed? vascular/AD pathologic profile. Vascular risk factors are easily identifiable and often modifiable, therefore, risk factor reduction could significantly reduce the incidence and prevalence of AD. Yet, specific vascular targets for AD prevention remain unclear. Proper cardiovascular regulation depends on an intact autonomic nervous system. Lower heart rate variability (HRV) is an index of autonomic dysfunction and is a significant predictor of CVD, abnormal prefrontal cortical activity, and impaired cerebral perfusion. However, its direct relationship to cognitive decline is poorly understood, and largely unexplored in racial/ethnic minority groups at disproportionately higher risk for both CVD and dementia. Furthermore, it is unknown if longitudinal decreases in HRV during mid- to late-life are associated with changes in cognitive performance, especially in the context of other subclinical and clinical CVD risk factors. Therefore, we will leverage the vast resources of the NIH-sponsored Multi-Ethnic Study of Atherosclerosis (MESA) to determine if lower HRV is associated with worse cognitive performance or longitudinal decline. MESA is ideal for this study because it is the only major cardiovascular cohort study in which high-risk racial/ethnic minority groups (African-American, Hispanic, and Chinese) comprise a majority of the baseline population, and in which longitudinal HRV and repeated cognitive data are already available. In Specific Aim 1 we hypothesize that lower measures of HRV indices obtained from a minimum of 3,271 participants at MESA Exam 1 (2000-2002) and Exam 5 (2010-2012) are significantly associated with scores on three cognitive tests administered at Exam 5 after adjustment for traditional CVD and AD risk factors. We further hypothesize in Specific Aim 2 that larger decreases in HRV values in the ~10-year period from Exam 1 to Exam 5 are associated with greater decline in cognitive performance in the 6-year period from Exam 5 to Exam 6 (2016-2018). We will determine if these associations differ by race and APOE ?4 allele carriage. The proposed analyses will provide important evidence to link reduced HRV to worse mid- to late-life cognitive performance in the context of a multi-ethnic study population with detailed assessments of subclinical and clinical CVD collected over 16+ years. Additionally, results could drive new standards of care for improving HRV prior to the onset of clinical CVD or cognitive decline.